1. Field of the Invention
This invention relates to biomedical devices, and more specifically relates to a method for coating a substrate with an antithrombogenic and/or an anti-infective agent.
2. Background of the Invention
Extensive investigations have been undertaken over many years to find materials that will be biologically and chemically stable toward body fluids. This area of research has become increasingly important with the development of various objects and articles which must be in contact with blood, such as artificial organs, vascular grafts, probes, cannulas, catheters and the like.
Synthetic plastics have come to the fore as preferred materials for such articles. However, these materials have the major drawback of being thrombogenic. In addition, devices such as catheters provide a pathway for entrance of microorganisms into the body and thus often are a source of infection. Accordingly, much effort has been directed toward methods to render plastic medical devices antithrombogenic and anti-infective.
Thrombogenicity has conventionally been counteracted by the use of anticoagulants such as heparin. Various procedures for attachment of heparin to otherwise thrombogenic polymeric surfaces have been disclosed. U.S. Pat. No. 4,521,564 to Solomon et al. discloses coating a polymeric article with an amine-rich surface and covalently conjugating aidehyde-actuated heparin to the amino groups thereof. Leininger et al., in U.S. Pat. No. 3,617,344 discloses a method in which a polymeric surface is chemically modified to include a chloromethyl group. Amination of the chloromethyl group provides a quarternary ammonium halide. Reaction of the halide with sodium heparin results in ionic bonding of the heparin to the surface.
A related approach has been described by Eriksson et al. in U.S. Pat. No. 3,634,123. An article having a plastic surface is heated to near or above its softening point in an aqueous solution of a cationic surface active agent, such as a long chain alkylamine or alkylenediamine hydrohalide. The solution is preacidified to a pH of 7.0 or lower. Subsequent digestion of the plastic article with an aqueous solution-of heparin results in an article having about 0.12 International Unit of heparin thereon. Improvements in the surface active agent method are described in U.S. Pat. No. 3,810,781 to Eriksson et al.; U.S. Pat. No. 4,349,467 to Williams et al.; U.S. Pat. No. 4,865,870 to Hu et al. and U.S. Pat. No. 4,713,402 to Solomon et al.
Attempts to solve the problem of infection have likewise been directed toward adherence of an antibacterial agent to the plastic article. Shepard et al., in U.S. Pat. No. 3,695,921, discloses dipping a catheter into a syrup containing a hydrophilic polymer and absorbing an antibiotic into the hydrophilic coating. Shepard et al. teach that most antibiotics are not sufficiently heat stable to be added to the syrup during the dipping step.
Fox et al. in U.S. Pat. No. 4,581,028, teaches infection resistant plastic medical articles, such as vascular grafts, having incorporated antimicrobial agents, such as silver sulfadiazine and pipericillin. The articles are prepared by dipping procedures.
Mustacich et al., in U.S. Pat. No. 4,479,795, discloses medical devices of permeable polymers including a releasably incorporated coating of a carboxylate antimicrobial agent. The device is made by a dipping process.
PCT published application no. WO 86/02561 teaches a medical device of a hydrophobic thermoplastic polymer having up to 1% chlorhexidine base coated thereon or incorporated therein.
McGary et al, in U.S. Pat. No. 4,678,660 discloses a method for preparing a polyurethane article having coated thereon a layer of polyurethane alloy containing a dispersed complex of a quaternary salt with either an antithrombogenic agent or an antibiotic. The method includes dipping the article in a solvent solution of the alloy.
Although all of the above disclosures have addressed the problems of infection and thrombogenesis during use of medical articles, satisfactory solutions have not yet been disclosed, particularly for medical articles, such as a catheter, to be introduced and advanced through body passages. In particular, there is a need for a method for preparation of medical articles coated with temperature sensitive materials which avoids dipping procedures using potentially toxic solvents. The present invention fulfills this need.